The FGF family of peptides are pleiotrophic growth factors which are potent stimulators of angiogenesis in both normal and pathologic conditions. The future development of anti-angiogenic therapies will undoubtedly focus of the rgulation of the FGF growth factors and their receptors. The long-term objective of this grant application is aimed at understanding the regulation of the FGF in microvascular diseases such as diabetic retinopathe, peripheral vascular occlusive disease, coronar artery disease, and in the recruitment of neovascularization associated with tumor angiogenesis. We have recently discovered the presence of soluble FGF receptors (also referred to as FGF binding proteins, or FGF-BPs) in the extracellular domain of the high affinity FGF receptor, FGFR-1. Even more recently, we have discovered that these proteins are present in blood and other biological fluids. These new and intrigning results have led us to hypothesize that the potent biological activities of the FGFs in vivo are regulated by these proteins. As part of this proposal, we will determine the biological activities and biochemical properties of the soluble FGF receptors. We will determine whether the soluble FGF receptors potentiate or inhibit the angiogenic properties of FGF-2 using three in vitro models of angiogenesis and one in vivo model. The angiogenic properties of FGF-2 will be examined using the rabbit corneal pocket model of angiogenesis. Agents which stimulate angiogensis, such as FGF-2, will be implanted into a small corneal pocket and the response will be quantitated using the imaging resources at the NCMIR. Quantiation will involve skeletonization of blood vessels and determination of their total area using software packages available at the NCMIR. We anticipate that these studies will provide tremendous insight into the role of the soluble FGF receptors in regulating the biological activity of the FGF and may lead to a paradigm shift in our understanding of FGF biology.
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